1. Field of the Invention
The invention concerns the fields of medicine and pharmaceutical research. Agents obtained with the invention are useful to treat chronic inflammatory conditions, in particular erosive arthritis and arteriosclerosis.
2. State of the Art
A chronic inflammatory disease is a medical condition which is characterized by persistent inflammation. Patients develop a chronic inflammatory disease because the immune system has an inappropriate response. Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. As well as rheumatoid arthritis and osteoarthritis, these diseases include arteriosclerosis and psoriatic arthritis.
Despite the prevalence of these diseases, there have been relatively few innovative breakthroughs into revealing their cause, providing treatment or curing approaches, despite intensive global research. In particular, rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that may affect many tissues and organs, but principally attacks synovial joints. About 1% of the world's population is afflicted by rheumatoid arthritis, with women being three times more often affected than men. The current pharmaceutical treatment mainly focuses on Analgesia to suppress pain, on immunosuppressive drugs to suppress inflammation (mainly glucocorticoids and disease-modifying anti-rheumatic drugs—DMARDs) and more recently on the selective inhibition of cytokines or pathogenic cell populations like B- or T cells.
Calcium homeostasis, thus the calcium level in the peripheral blood, is regulated very narrowly and deregulation can cause serious clinical disorders, including heart failure. The cell surface calcium receptor is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Activation of this receptor by extracellular calcium ions inhibits PTH secretion whereas blocking the calcium receptor stimulates secretion of PTH. Chronically elevated levels of PTH, as they occur in hyperparathyroidism, stimulate bone resorption whereas temporary increases in circulating levels of PTH stimulate bone formation. A proposed approach to treat osteoporosis is based on the use of small, orally active compounds which block the calcium receptor thereby increasing the circulating levels of endogenous PTH. Compounds acting as inhibitors of the calcium receptor are termed Calcilytics. Several patent publications propose the use of calcium receptor inhibitors for the treatment of osteoporosis, osteoarthritis and/or rheumatoid arthritis (e. g. WO2009001214, WO2008041118, U.S. Pat. No. 7,211,685 and U.S. Pat. No. 6,916,956).
Most of these calcium receptor inhibitors act on the calcium sensing receptor (CaSR) of the parathyroid gland and other tissue. As Calcilytics interfere with calcium homeostasis, their administration has to be controlled very carefully.
GPRC6A (G-protein coupled receptor family C group 6 member A) is a receptor that functions as a sensor of L-amino acids, but also binds divalent cations, including Calcium.